A new mechanisms of G-CSF effect against myocardial infarction - molecular mechanism of healing process acceleration -

G-CSF抗心肌梗塞的新机制-加速愈合过程的分子机制-

• 批准号: 16590670
• 负责人: MINATOGUCHI Shinya
• 金额: $ 2.3万
• 依托单位: GIFU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590670/
• 关键词: G-CSF; Acceleration of healing process; MMP-9; MMP-1; macrophage; 心筋再生; 梗塞サイズ; fibrosis; 左室利モデリング; 心機能

The purpose of the present study was to define whether the improvement of cardiac function and remodeling after infarction (MI) by G-CSF relates to acceleration of the healing process from absorption of necrotic tissues into granulation and then scarring, in addition to myocardial regeneration. In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 μg/kg/day of human recombinant G-CSF (G) was subcutaneously injected from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction and thicker infarct-LV wall were seen in G at 3 months after MI. At 2 days, 7 days, 14 days and 3 months after MI, necrotic tissue areas were 14.2±1.5/13.4±1.1, 0.4±0.1/1.8±0.5^*, 0/0 and 0/0 mm^2/slice/kg, granulation areas 0/0, 4.0±0.7/8.5±1.0^*, 3.9±0.8/5.7±0.7^* and 0/0 mm^2/slice/kg, scar areas 0/0, 0/0, 0/0 and 4.2±0.5/7.9±0.9^* mm^2/slice/kg in G and S, respectively (^* : p<0.05,G vs S). Clear increases of macrophages with positive RAM 11 and of matrix metalloproteinase (MW) 1 and 9 were seen in G at 7 days after MI. This suggests that G accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs. Meanwhile, survived myocardial tissue areas within the risk areas were significantly increased in G despite no significant difference in LV weight, LV wall area and size of cardiomyocytes between G and S. Confocal microscopy revealed significant increases of cardiomyocytes with positive DiI (a marker of bone marrow cells) and positive troponin I (a marker of cardiomyocytes) or CD-31 (a marker of endothelial cells) in G, suggesting enhanced myocardial regeneration by G. In conclusion, the acceleration of the healing process as well as myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.

本研究的目的是确定G-CSF改善心肌梗死（MI）后的心脏功能和重塑是否与加速愈合过程（从坏死组织吸收到肉芽组织，然后形成瘢痕）以及心肌再生有关。在30分钟冠状动脉闭塞和再灌注兔模型中，在MI后1至5天皮下注射生理盐水（S）或10 μg/kg/天的人重组G-CSF（G）。MI后3个月，G组左室内径缩小，左室射血分数增加，梗死左室壁增厚。MI后2天、7天、14天和3个月，坏死组织面积分别为14.2±1.5/13.4±1.1、0.4±0.1/1.8±0.5^*、0/0和0/0 mm^2/切片/kg，肉芽面积为0/0、4.0±0.7/8.5±1.0^*、3.9±0.8/5.7±0.7^* 和0/0 mm^2/切片/kg，瘢痕面积分别为0/0、0/0、0/0和4.2±0.5/7.9±0.9^* mm^2/切片/kg（G vs S，p<0.05）。MI后7天，G组RAM 11阳性巨噬细胞和基质金属蛋白酶（MW）1和9明显增加。这表明G通过增加巨噬细胞加速坏死组织的吸收，并通过表达MMP减少肉芽组织和瘢痕组织。与此同时，尽管左室重量、左室壁面积和心肌细胞大小在G组和S组之间无显著差异，但G组危险区内存活心肌组织面积显著增加。共聚焦显微镜显示，G中DiI（骨髓细胞标志物）和肌钙蛋白I（心肌细胞标志物）或CD-31（内皮细胞标志物）阳性的心肌细胞显著增加，表明G增强了心肌再生。总之，愈合过程的加速以及心肌再生可能对MI后G-CSF治疗的有益作用起重要作用。

项目成果

心臓病-診断と治療の最前線

心脏病——诊断和治疗的前沿

• 发表时间: 2004
• 作者: 湊口信也;藤原久義
• 通讯作者: 藤原久義

Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment

• DOI: 10.1161/01.cir.0000129770.93985.3e
• 发表时间: 2004-06-01
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Minatoguchi, S;Takemura, G;Fujiwara, H
• 通讯作者: Fujiwara, H

Acceleration of the healing process and myocardial regeneration may be important a mechanism of ---

加速愈合过程和心肌再生可能是重要的机制——

• 发表时间: 2004
• 期刊: Circulation 109
• 作者: Isobe M;Kosuge H;Koga N;Futamatsu H;Suzuki J;Shimosawa T et al.;Watanabe H. et al.;Minatoguchi et al.
• 通讯作者: Minatoguchi et al.